Ca antagonists (CAts) interfere with the role of Ca as a second messenger. Although they have the potential to suppress the activity of many cell types they are proving to be extremely effective in the treatment of cardiovascular disorders related to hyperactivity, such as coronary and cerebral atery spasm and supraventricular tachycardia. This is only the beginning of the clinical use of organic CAts. Their full therapeutic potential however can only be realized once their mechanism of action has been elucidated and the basic reasons for CAt selectivity are understood. This research proposal addresses these objectives. The most popular theory holds that CAts produce vasodilation by inhibition of Ca influx. However a number of recent reports suggest alternative theories such as (1) inhibition of intracellular Ca release; (2) stimulation of Na, Ca exchange; (3) inactivation of calmodulin. We propose to establish the mechanism of action for three CAts (D-600, diltiazem, and nisoldipine) and investigate if any why they exhibit selective potencies for in hibition of various arteries. We will measure CAt effects on (1) Ca influx stimulated by depolarization and Alpha-adrenergic receptor activation; (2) Ca extrusion during and following stimulation; (3) Ca release from intracellular Ca stores; (4) Ca release from extracellular binding sites; (5) Ca sensitivity of smooth muscle myofilaments in skinned smooth muscle; (6) SR uptake and release of Ca also in skinned smooth muscle. The main preparation will be the isolated rabbit aorata. Studies will also be done on rabbit mesenteric conduit and resistance arteries, coronary arteries and the basilar artery in order to elucidate mechanisms of CAt selectivity. The anticipated results will identify the different arterial Ca channels and their sensitivity to CAt blockade, establish the mechanism of CAt action at therapeutic drug levels and identify potential intracellular receptor sites for D-600, diltiazem, and nisolidipine.